J Neurosurg Case Lessons 1(26):CASE21176, 2021 DOI: 10.3171/CASE21176

Surgical treatment of common peroneal neuropathy in schwannomatosis: illustrative cases

Robert Y. North, MD, PhD,1 Rita Snyder, MD,2 John M. Slopis, MD,3 and Ian E. McCutcheon, MD1

Departments of 1Neurosurgery and 3Neuro-, The University of Texas MD Anderson Cancer Center, Houston, Texas; and 2Department of , Baylor College of , Houston, Texas

BACKGROUND Neurofibromatosis syndromes such as neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis often result in painful symptoms related to tumor burden. OBSERVATIONS Painful symptoms classically associated with common points of peripheral nerve entrapment, such as common peroneal neuropathy at the fibular tunnel, may present in patients both with and without focal tumor involvement. LESSONS Surgical decompression at the point of entrapment, with or without resection of tumor, may provide symptomatic relief. Examples of surgical decompression at the point of entrapment, both with and without resection of tumor, are presented.

https://thejns.org/doi/abs/10.3171/CASE21176 KEYWORDS schwannomatosis; common peroneal nerve; peroneal tunnel syndrome; double-crush syndrome; peripheral nerve entrapment

Schwannomatosis is the least common of the neurofibromatosis surgical treatment of two patients with an established diagnosis of syndromes, affecting approximately 1 in 126,000 people.1 It is char- schwannomatosis and painful common peroneal neuropathy due to acterized by multiple in the absence of vestibular entrapment at the fibular tunnel. The cases illustrate examples of nerve involvement and is clinically and biologically distinct from neu- how schwannomatosis may lead to an entrapment neuropathy due to rofibromatosis types 1 and 2.2 For patients with schwannomatosis, either a small, focal tumor within the nerve or mild thickening of the pain is the most common presenting symptom leading to diagnosis nerve at a point of nerve constriction (such as the fibular tunnel), and is a leading cause of disability, and nearly 70% of patients report leading to painful neuropathy. These patients underwent decompres- suffering from chronic pain.3 Chronic pain in schwannomatosis is sion of the common peroneal nerve at the fibular tunnel with removal often multifactorial but dominated by neuropathic pain related to of any identifiable focal tumor; both obtained a good clinical result schwannomas, with the overall tumor burden significantly associated with symptomatic relief and no neurological detriment. with the severity of patient-reported pain.4 However, despite the rela- tionship of tumor burden to overall pain and the frequent correlation Illustrative Cases of specific tumors to localizing painful symptoms, focal tumor burden Case 1 does not always correlate with a patient’sspecific painful symp- History, Physical Examination, Imaging Findings toms.5,6 Surgical treatment of painful symptoms in schwannomatosis A 46-year-old man presented with a past medical history of often focuses on the resection of symptomatic tumors.5,7,8 However, schwannomatosis, chronic lower back pain, and multifocal neuro- when considering surgical treatments in this patient population, partic- pathic pain associated with multiple nerve tumors and the sequelae ularly for localizing neuropathic pain, it is critically important to con- of prior surgical treatments for painful schwannomas. He had under- sider other etiologies, such as entrapment neuropathies, in addition gone more than 10 prior resections of painful nodular tumors over to focal symptomatic tumors. Here, we present cases detailing the the previous 30 years. Each of these resected tumors was a benign

ABBREVIATIONS MRI = magnetic resonance imaging; VAS = visual analog scale. INCLUDE WHEN CITING Published June 28, 2021; DOI: 10.3171/CASE21176. SUBMITTED April 2, 2021. ACCEPTED April 6, 2021. © 2021 The authors, CC BY-NC-ND 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Unauthenticated | Downloaded 09/25/21 08:58 PM UTC FIG. 2. Postcontrast MRI (axial T1-weighted) of right lower extremity, with arrows pointing to the common peroneal nerve at the fibular head. Left: Case 1 without evidence of focal tumor. Right: Case 2 with a small focal tumor.

On physical examination, he had no neurocutaneous markings or skin changes, no palpable nodules along the major nerves of the upper or lower limbs, and normal muscle bulk in the legs. His neu- rological examination showed normal ankle dorsiflexion, eversion and inversion of the foot, extension of toes, and ankle plantarflex- ion. He also exhibited no loss of sensation in the lower limbs. He did have a positive Tinel’s sign just below the right fibular head. The patient’s clinical examination and history appeared most con- sistent with a painful neuropathy of the common peroneal nerve. Review of multiple prior magnetic resonance imaging (MRI) studies of his spine and lower extremities revealed numerous nerve sheath tumors consistent with his diagnosis of schwannomatosis, but none were located within the right distal thigh or proximal right lower extremity to explain his focal pain (Fig. 2 left). After a discussion of treatment options, including decompression of the common pero- neal nerve at the fibular head, spinal cord stimulation, and resection of nerve sheath tumors within the proximal sciatic nerve, he under- went decompression of the common peroneal nerve in conjunction with resection of several other disparate painful, nodular schwanno- mas, including a large tumor arising from an intercostal nerve on the right chest wall.

Operation The patient was positioned in a left lateral decubitus position to facilitate resection of a arising from the right sixth intercostal nerve in addition to decompression of the right common peroneal nerve. The latter was addressed through a 4-cm diagonal FIG. 1. Whole-body pain map annotated by the patient in case 1. incision just below the fibular head. The nerve was easily identified, coursing around the anterolateral aspect of the fibular head. We inserted a #4 Penfield dissector into the fibular tunnel to follow the schwannoma. At his presentation to the multidisciplinary neurofibro- course of the nerve distally and found that the nerve was tightly matosis clinic at the MD Anderson Cancer Center, the patient noted compressed within the tunnel. The nerve was diffusely thickened multiple sites of pain, but his most bothersome symptom was a but without focal nodularity or evidence of schwannoma (Fig. 3 left). focal area of severe pain affecting the anterolateral right lower leg, We cut the overlying ligamentous and fascial band and, in this fash- from just below the knee to just above the ankle joint (Fig. 1). This ion, completely freed the nerve from further pressure in this loca- pain was intermittent, present for more than 1 year, and rated at a tion. The articular branch was identified and preserved. Direct severity of 8 of 10 on the visual analog scale (VAS). It was sharp intraoperative ultrasound showed no hypoechogenic foci, confirming and burning in character, without specific aggravating or alleviating the absence of occult tumor within the diffusely enlarged nerve. triggers and without any radiating pain proximal or distal to the area. Previous treatments of his chronic right leg pain included lam- Postoperative Course inectomy for resection of a right L5–S1 schwannoma, lumbar epidu- After , the patient had complete and immediate resolution ral steroid injections, lumbar sympathetic nerve blocks, and of the right anterolateral leg pain (0 of 10 on the VAS) without sen- comprehensive medical with multiple neuromodu- sory or motor deficits. At his last follow-up 2 years after the surgery, latory medications. he remained free of his prior lateral right lower leg pain.

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Unauthenticated | Downloaded 09/25/21 08:58 PM UTC FIG. 3. Artist’s rendering of surgical exposure and intraoperative findings with hypertrophy of the superficial peroneal nerve without any evidence of focal tumor (left) and with a focal tumor of the superficial peroneal nerve within the fibular tunnel (right).

Case 2 bands above the dissector to expose the nerve as it coursed distally. History, Physical Examination, Imaging Findings The tumor capsule was incised and dissected off the tumor to enable A 59-year-old woman with a past medical history of dermatomyo- a subcapsular removal, and single entering and exiting fascicles to sitis, lymphocytic colitis, and schwannomatosis presented with chronic and from the tumor were identified. The fascicles were coagulated and abdominal pain and neuropathic pain affecting her right face and right cut, and the tumor was gently elevated en bloc. lower leg. The patient had undergone prior resection of multiple schwannomas from the right arm and left upper thigh. She developed Postoperative Course bothersome pain affecting the anterolateral right lower leg, starting The patient was admitted overnight for pain control and periopera- just below the knee and radiating down the tibia. The pain in her right tive intravenous antibiotics. She had prompt and significant improve- lower leg was similar in character to pain relieved by prior resection ment of the right anterolateral leg pain and no sensory or motor of schwannomas and was inadequately controlled with medical man- deficits. She remained without recurrence of pain at the last follow-up agement. On physical examination, the patient had a small superficial 18 months after surgery. palpable schwannoma on the right anterior lower leg and normal muscle bulk in her legs. Ankle dorsiflexion, eversion and inversion of Discussion the foot, extension of toes, and ankle plantarflexion all showed full ’ Observations strength. Sensation was intact in the right leg, and Tinel ssignwas fi positive on the anterior aspect of the fibula just below the fibular Surgical treatment of pain in patients with neuro bromatosis/schwan- head. As in case 1, the patient’s clinical examination and history sug- nomatosis syndromes is often complicated by challenging diagnostic gested a painful common peroneal neuropathy. MRI revealed a con- dilemmas. Combinations of simultaneous, related peripheral nerve and trast-enhancing nerve sheath tumor 3 mm in diameter, located in the spinal nerve tumors, or multiple tumors along the course of a single fi fi vicinity of the fibular head and anatomically consistent with her focal peripheral nerve can make it dif cult to de ne the symptomatic lesion. pain syndrome (Fig. 2 right). The patient underwent decompression Additionally, recurrent or refractory pain may arise from a combination of of the common peroneal nerve with resection of a small schwannoma tumor burden, sequelae of prior treatments, and/or additional diagnoses arising from a single fascicle within the common peroneal nerve (Fig. such as an intrinsic or entrapment neuropathy. 3 right). Operative details and postoperative course are summarized The etiology of a painful focal neuropathy in the presence of a readily fi below. identi able, isolated lesion (such as a tumor) appears intuitive; however, in cases without a focal lesion, the etiology is less clear. Hypertrophy of Operation nerves may be diffuse or segmental, and it is often seen in patients with The patient was positioned supine with a roll placed underneath neurofibromatosis type 1 and occasionally in those with schwannomato- her right hip, internally rotating the right leg and providing easy access sis. It is important to note that the absence of tumor by palpation or by to the anterolateral aspect of the right lower leg. In addition to the ultrasonography does not completely exclude the possible presence of lower extremity surgery, the patient also underwent resection of two one or more occult tumors within a segment of thickened nerve. In case schwannomas of the anterior chest wall. As in case 1, a 4-cm diagonal 2, biopsy of the nerve was not done because of a concern that it would incision at the junction between the fibular head and fibular shaft cause injury to nerve fascicles, local fibrosis, and neuroma formation that exposed the common peroneal nerve just proximal to the fibular tun- could cause pain in the future. In neurofibromatosis type 2, a peripheral nel. Opening of the fascia overlying the tunnel revealed a focal, round polyneuropathy causing axonal sensory dysfunction is well described irregularity in the nerve consistent with the tumor seen on MRI at the and can cause focal thickening, both in the dorsal root ganglia and in proximal segment of the fibular tunnel. To protect the nerve, we more distal segments of peripheral nerves, due to small endoneurial inserteda#4Penfield dissector into the tunnel and cut the fascial tumorlets and diffuse proliferation of Schwann cells and/or perineurial

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Unauthenticated | Downloaded 09/25/21 08:58 PM UTC cells.9,10 Although a similar phenomenon is likely in schwannomatosis, it References has not been described to date, to the best of our knowledge. 1. Evans DG, Bowers NL, Tobi S, et al. Schwannomatosis: a genetic In addition to neuropathy from isolated, severe lesions affecting the and epidemiological study. J Neurol Neurosurg . involved peripheral nerve, some authors have proposed that symptomatic 2018;89(11):1215–1219. fi peripheral neuropathies may also result from a combination of less 2. Baser ME, Friedman JM, Evans DG. Increasing the speci city of diagnostic criteria for schwannomatosis. . 2006;66 severe multifocal lesions, with or without additional systemic disease (like – 11 (5):730 732. diabetes mellitus) affecting the function of the nerve. Upton and 3. Merker VL, Esparza S, Smith MJ, et al. Clinical features of schwan- McComas first proposed such a “double-crush” phenomenon as it related nomatosis: a retrospective analysis of 87 patients. Oncologist. to cervicothoracic spine with concomitant carpal or cubital tun- 2012;17(10):1317–1322. nel syndrome in 1973,11 and numerous other authors have since added 4. Merker VL, Bredella MA, Cai W, et al. Relationship between whole- clinical evidence supporting such a phenomenon.12–16 The notion that a body tumor burden, clinical phenotype, and quality of life in patients fi – similar double crush applies for simultaneous focal neuropathies in the with neuro bromatosis. Am J Med Genet A. 2014;164A(6):1431 1437. 5. Gonzalvo A, Fowler A, Cook RJ, et al. Schwannomatosis, sporadic lower extremities is also well supported.17,18 In essence, each of the schwannomatosis, and familial schwannomatosis: a surgical series cases we describe here is likely an example of double crush in the con- with long-term follow-up. Clinical article. J Neurosurg. 2011;114(3): text of schwannomatosis, and it is certainly conceivable that exactly anal- 756–762. ogous clinical scenarios may arise in patients with neurofibromatosis type 6. Ostrow KL, Donaldson KJ, Caterina MJ, et al. The secretomes of 1 as well. It is difficult to know whether the nerve enlargement (whether painful versus nonpainful human schwannomatosis tumor cells dif- caused by hypertrophy or schwannoma) is sufficient to cause a fibular ferentially influence sensory neuron gene expression and sensitivity. tunnel syndrome in a tunnel of normal caliber or whether the additional Sci Rep. 2019;9(1):13098. 7. Halvorsen CM, Rønning P, Hald J, et al. The long-term outcome presence of ligamentous thickening may contribute to the insufficiency ’ after resection of intraspinal nerve sheath tumors: report of 131 con- of the tunnel s cross-sectional area relative to that of the nerve tra- secutive cases. Neurosurgery. 2015;77(4):585–593. versing it. 8. Huang JH, Simon SL, Nagpal S, et al. Management of patients with schwannomatosis: report of six cases and review of the literature. Surg Neurol. 2004;62(4):353–361. € Lessons 9. Godel T, Baumer P, Farschtschi S, et al. Peripheral nervous system fi alterations in infant and adult neurofibromatosis type 2. Neurology. Management of chronic pain in patients with neuro bromatosis – fi 2019;93(6):e590 e598. syndromes represents a signi cant clinical challenge but remains a 10. Hagel C, Lindenau M, Lamszus K, et al. Polyneuropathy in neurofi- central aspect of their medical care. Our cases demonstrate exam- bromatosis 2: clinical findings, molecular genetics and neuropatho- ples of common peroneal neuropathy due to entrapment in the fibu- logical alterations in sural nerve biopsy specimens. Acta Neuro- lar tunnel in patients with schwannomatosis: one with a small tumor pathol. 2002;104(2):179–187. (3-mm diameter) and one without an identifiable tumor. Common 11. Upton AR, McComas AJ. The double crush in nerve entrapment – peroneal neuropathy is the most common mononeuropathy of the syndromes. Lancet. 1973;2(7825):359 362. lower extremity.19 Most often associated with an entrapment syn- 12. Baba H, Maezawa Y, Uchida K, et al. Cervical myeloradiculopathy fi with entrapment neuropathy: a study based on the double-crush drome at the bular head, common peroneal neuropathy has a vari- concept. Spinal Cord. 1998;36(6):399–404. ety of etiologies, including significant weight loss, external compression, 13. Galarza M, Gazzeri R, Gazzeri G, et al. Cubital tunnel surgery in posture-related stretch injury, trauma, and local mass effect from benign patients with cervical radiculopathy: double crush syndrome? Neu- or malignant sporadic tumors.20–23 For appropriately selected patients rosurg Rev. 2009;32(4):471–478. with such entrapment, surgical decompression of the common peroneal 14. Hurst LC, Weissberg D, Carroll RE. The relationship of the double nerve yields symptomatic (motor and/or pain) improvement in up to crush to carpal tunnel syndrome (an analysis of 1,000 cases of car- pal tunnel syndrome). J Hand Surg Br. 1985;10(2):202–204. 80%–90% of patients.20,24 Both of the patients presented here had a 15. Narakas AO. The role of thoracic outlet syndrome in the double good clinical result. However, the effectiveness of surgery in patients crush syndrome. Ann Chir Main Memb Super. 1990;9(5):331–340. with schwannomatosis may be less assured than in the general popula- 16. Richardson JK, Forman GM, Riley B. An electrophysiological explo- tion. It has been reported that nearly 30% of surgical treatments for pain ration of the double crush hypothesis. Muscle Nerve. 1999;22(1): in a schwannomatosis cohort saw no significant improvement.3 Although 71–77. the incidence of entrapment neuropathies and the overall effectiveness 17. Ang CL, Foo LS. Multiple locations of nerve compression: an of a peroneal tunnel release in patients with neurofibromatosis syn- unusual cause of persistent lower limb paresthesia. J Foot Ankle Surg. 2014;53(6):763–767. dromes remain unclear, this report does offer examples of marked and 18. Augustijn P, Vanneste J. The tarsal tunnel syndrome after a proxi- sustained improvement in patient symptoms from decompression and mal lesion. J Neurol Neurosurg Psychiatry. 1992;55(1):65–67. resection and from decompression alone. Entrapment neuropathies, 19. Katirji MB, Wilbourn AJ. Common peroneal mononeuropathy: a clin- such as common peroneal entrapment at the fibular head, both with ical and electrophysiologic study of 116 lesions. Neurology. and without an identifiable tumor, should not be discarded in developing 1988;38(11):1723–1728. a differential diagnosis for a painful extremity in patients with neurofibro- 20. Kim DH, Murovic JA, Tiel RL, Kline DG. Management and out- matosis and may be amenable to surgical treatment. Although the comes in 318 operative common peroneal nerve lesions at the Lou- fi isiana State University Health Sciences Center. Neurosurgery. observations made here are limited to patients with a neuro bromatosis 2004;54(6):1421–1429. syndrome, the lesson that very small mass lesions at points of nerve 21. Spinner RJ, Hebert-Blouin MN, Amrami KK, Rock MG. Peroneal entrapment may lead to significant symptoms is readily applicable to and tibial intraneural ganglion cysts in the knee region: a technical patients without an underlying neurocutaneous syndrome. note. Neurosurgery. 2010;67(suppl operative 3):ons71–ons78.

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Unauthenticated | Downloaded 09/25/21 08:58 PM UTC 22. Psimaras D, Lenglet T, Maisonobe T, et al. Monocenter clinical and Author Contributions neurophysiological study of 231 patients with peroneal neuropathy. Conception and design: North, McCutcheon. Acquisition of data: Neurology. 2012;78(suppl 1):P04.024. North, Slopis, McCutcheon. Analysis and interpretation of data: North, 23. Rubin DI, Kimmel DW, Cascino TL. Outcome of peroneal neuropa- Slopis, McCutcheon. Drafting the article: North. Critically revising the thies in patients with systemic malignant disease. Cancer. article: North, Slopis, McCutcheon. Reviewed submitted version of 1998;83(8):1602–1606. manuscript: all authors. Approved the final version of the manuscript 24. Humphreys DB, Novak CB, Mackinnon SE. Patient outcome after on behalf of all authors: North. Administrative/technical/material common peroneal nerve decompression. J Neurosurg. 2007;107(2): support: McCutcheon. Study supervision: McCutcheon. Medical 314–318. illustrations: Snyder.

Disclosures Correspondence The authors report no conflict of interest concerning the materials or Robert Y. North: The University of Texas MD Anderson Cancer Center, methods used in this study or the findings specified in this paper. Houston, TX. [email protected].

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